MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines [MAIT]

Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses, with reactogenicity influencing their use during and beyond the COVID-19 pandemic. However, despite the clinical significance, the underpinning mechanisms remain unclear. Innate and innate-like lymphocytes, such as mucosal-associated invariant T cells, are highly sensitive to cytokines and can enhance both innate and adaptive vaccine responses. We compared longitudinal human immune responses and reactogenicity following homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination to define the interactions between innate-like lymphocytes and adaptive immunity – and their in vivo consequences. Specifically, Ad vector priming elicited robust early type I interferon (IFN)-mediated activation of innate-like T cells, augmenting T cell responses (innate to adaptive signalling), which diminished upon boosting in the presence of anti-vector immunity. In contrast, mRNA vaccine responses in innate-like cells were markedly enhanced after boosting. This was initiated by IFN-γ signalling from spike-specific memory T cells and amplified by IFN-γR+ innate-like lymphocyte networks (adaptive to innate signalling). Importantly, extending the interval between doses reduced inflammatory responses to mRNA vaccination. In an independent clinical trial, spike-specific T cells predicted severe reactogenicity to mRNA vaccine boosting regardless of the dosing interval and vaccine type. These findings reveal a close integration of innate-like and adaptive responses to novel vaccines, including an IFN-γ-mediated function of innate-like T cells in orchestrating critical early responses to mRNA vaccines which may have significant implications for optimising future vaccine regimens.